25 A CONVERGENCE OF APPROACHES FOR THERAPEUTIC RESEARCH Transforming knowledge in life sciences into innovative medicines A CONVERGENCE OF APPROACHES FOR THERAPEUTIC RESEARCH

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27 MESSAGE FROM THE CHAIRMAN Life sciences have gone through dramatic advances over the last decade. However, a large number of therapeutic needs remains unmet. While an ageing population and the increasing incidence and prevalence of severely debilitating diseases represent a critical global challenge, it is the responsibility of healthcare stakeholders to mobilize resources, skills, knowledge and creativity to discover, develop and bring to market innovative medicines. With a legacy of 80 years of pharmaceutical activity, a R&D budget equivalent to 20% of its consolidated sales and a world-renowned expertise in advanced technology platforms, Ipsen is particularly well positioned to spearhead innovative patient care. The location of its four R&D centers (Paris, Boston, Barcelona, London) gives Ipsen a competitive edge in gaining access to leading university research teams and highy qualified personnel. Ipsen s research is focused on four main disease areas: oncology, endocrinology, neurology and haematology. Across those therapeutic areas, Ipsen benefits from proven platform expertise in the engineering of peptides, proteins and steroids, as well as advanced delivery systems. Our R&D efforts are strengthened from collaboration programmes with university researchers and industry leaders. The numerous agreements with leading institutions and organizations confirm Ipsen s commitment to innovation and reaffirm the company s ability to work with academic centres of excellence to transform knowledge into innovative medicines. We at Ipsen hold a fundamental belief in the fact that academic and pharmaceutical R&D must be collaborative to succeed. The description and analysis of our pipeline emphasize our ambition to provide physicians and patients with the best treatments. Jean-Luc Bélingard, Chairmain and CEO, Ipsen Group 24 25

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29 AN INTEGRATED APPROACH TO DISCOVERY AND INNOVATION RESTORING PHYSIOLOGICAL BALANCE THROUGH THE CONVERGENCE OF TECHNOLOGICAL PLATFORMS 26 27

30 AN INTEGRATED APPROACH TO DISCOVERY AND INNOVATION RESTORING PHYSIOLOGICAL BALANCE Ipsen s research is focused on the fundamental concept of homeostasis: loss or gain of molecular/biological functions can lead to life-threatening diseases, thus the need to restore and sustain physiological balance through the control of chemical messengers such as hormones and neurotransmitters. Ipsen s approach to diseases consists in restoring physiological levels to their precise and appropriate balance through the enhancement or the suppression of biological functions. For instance, number of statural or endometabolic disorders, as well as haemostasis or tissue injury, result from a functional deficiency in growth factors such as GH, IGF-I, gut peptides such as GLP-1 or ghrelin, or haemostatic agents such as factor VIII respectively. Ipsen s research aims at compensating for these deficiencies with analogs of the natural biological effectors. On the opposite, other diseases such as hormone dependent cancers, movement disorders (spasticity) and other endometabolic conditions result from an excess of chemical messengers: growth factors (GH, prolactin, insulin), neuropeptides (ACTH...), steroids (estrogens, androgens) or neurotransmitters (acetylcholine). Ipsen s objective is then to modulate the level of these substances in order to restore the biological imbalance in the local milieu.

31 THROUGH THE CONVERGENCE OF TECHNOLOGICAL PLATFORMS Ipsen s well differentiated expertise results from the integration of several skills for the conception of novel patentable chemical entities optimized towards drugable hormonal targets. Critical to this process are the following technologies: Pharmacogenomics and genetics Peptides, proteins and steroids engineering Advanced drug delivery systems Early in the discovery process, emphasis is placed on the identification of clinically relevant markers. They will facilitate the access and the treatment of patient population enriched in responders as well as the definition of the optimal dosing regimen in order to design suitable formulations and delivery systems that will ensure patient compliance and convenience

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33 THERAPEUTIC ADVANCES TO ADDRESS MEDICAL NEEDS Ipsen s expertise in hormone dependent diseases gives the Group a capacity to identify and test original targets to support its core franchises such as endocrinology, oncology and neurology. HORMONES TECHNOLOGICALLY INTEGRATED PLATFORMS EXAMPLES 30 31

34 THERAPEUTIC ADVANCES TO ADRESS MEDICAL NEEDS HORMONES as well defined and understood templates with matching targets In spite of major advances in molecular and cellular biology, the selection of credentialized or unprecedented targets is always a difficult choice. This risk is however mitigated as far as hormonal therapies are concerned, while providing for a wide scope of therapeutic opportunities through four mechanistic pathways: 1- endocrine i.e. blood circulating hormones acting at a distance from their glandular sources (e.g insulin); 2- paracrine i.e. hormones synthesized in and released from endocrine cells bind to their receptors in nearby cells and affect their functions; 3- autocrine i.e. hormones bind to their receptors on, and affect the function of, the cell type that produced them; 4- intracrine i.e. hormones that act inside a cell. TECHNOLOGICALLY INTEGRATED PLATFORMS Ipsen s originality lies within the convergence of: medicinal chemistry applied to steroids, peptides and protein engineering, each with its own toolbox such as molecular modelling, but always based on rationale design as opposed to random screening, and an expertise in advanced delivery systems, which aims at developing: Vectorized agents associating an active moiety to an appropriate ligand for the targeted tissue and for intracellular delivery with the objective to increase efficiency and efficacy while sparing or minimizing toxic effects to the non-target tissues. Controlled delivery systems for enhanced patients convenience and quality of life.

35 EXAMPLES: Combination therapies, chimeras and Endo-metabolism NEW TARGETS: REVISITING THE CLASSICS Ipsen s expertise in the biosynthesis of steroids has enabled the Group to explore new pathways, such as the steroid sulfatase enzyme inhibitors. This family of enzyme is key in the conversion of steroids sulfate into their biologically active form. The fact that key steroid intermediates are being stored in the form of sulfate has not been fully appreciated until the identification of biosynthetic pathways that are critical in the release of estrogenic and androgenic substances in target organs. Ipsen has experimentally validated the contributory role of the sulfatase enzyme as a diagnostic and prognostic factor for breast, ovarian, prostate and endometrial cancers, and developed an inhibitor which is now being evaluated clinically. COMBINATION THERAPIES AND CHIMERAS Short stature Combination therapies have been widely used in the treatment of HIV as well as in oncology. Ipsen s approach consists in applying such combination therapies to endocrinology, either as a physical association or as specifically designed compounds bearing multiple pharmacological entities. For instance, in the treatment of short statures, it is established that children suffering from organic growth hormone deficiency should be treated with rhgh, whereas patients with severe primary IGFD should be treated with rhigf-i. However, between these two extreme conditions, some patients suffer from Idiopathic Short Stature (ISS). Ipsen is developing a combination therapy associating GH and IGF-I to provide these children with a therapeutic solution

36 THERAPEUTIC ADVANCES TO ADRESS MEDICAL NEEDS EXAMPLE: Combination therapies, chimeras and Endo/metabolism In November 2007, Celera and Ipsen entered into a research collaboration to develop means to predict the response of short stature children to a specific treatment. The initial phase of the collaboration will focus on the identification and characterization of genetic markers relating to this condition. Assuming the first phase of this collaboration is completed successfully, the next goal will be to develop diagnostic assays to be validated during clinical trials by Ipsen. If successful, these trials would form the basis for commercial companion diagnostic tests to Ipsen s short stature therapies. This collaboration between diagnostic and a pharmaceutical companies aims at improving therapeutic availability through the practice of personalized disease management. The potential outcomes from this partnership could lead to the development of tests to support the rationale use of Ipsen s medicines in broader indications for short stature. Pituitary adenomas Ipsen has synthesised a novel chimeric compound, dopastatin, which combines a somatostatin analogue and a dopamine agonist to achieve a synergic therapeutic effect in the treatment of pituitary adenoma such as acromegaly, as well as neuroendocrine tumours. The Group is currently studying this molecule whose spectrum of activity is wider than that of commercial somatostatin analogues. Ipsen hopes it will reach beyond symptomatic treatment to achieve tumor regression thus providing a therapeutic alternative to surgery for these patients who are poor responders to conventional therapy. pharmacological activities to protect neuronal mitochondria (the intracellular organelles responsible for the production of energy) in connection with neurodegenerative conditions, such as Parkinson s and Huntington s diseases or amyotrophic lateral sclerosis. Metabolism By leveraging its technology platforms mostly in the area of peptide engineering and advanced delivery systems, Ipsen has built world class expertise in the area of metabolic diseases with lead drug candidates for the treatment of: diabetes: GLP-1 and GIP; both incretins able to stimulate the release of insulin upon elevated level of dietary sugars and lipids; feeding disorders such as cachexia (ghrelin agonists); obesity (MSH/MC4) and control of diabetes. Taspoglutide was selected from a family of long-acting glucagons-like peptide-1 (GLP-1) analogues with structural modifications of the original human sequence which confer intrinsic controlled release properties ranging from once a day to twice a month. Taspoglutide is being developped as an innovative treatment for patients with type 2 diabetes mellitus, the fourth leading cause of death in most developped countries. Roche exercised its option to license Taspoglutide from Ipsen in 2006 and acquired exclusive worldwide rights with the exception of Japan and France (co-marketing ). Roche moved this drug into phase III clinical trials in June Neurodegenerative diseases For neurodegenerative conditions, Ipsen has designed several chimeric compounds, i.e. compounds endowed with several

37 In Japan, Ipsen s partner Teijin jointly with Chugai is conducting phase II clinical trial. Besides, Ipsen is exploring the role of other gut or brain peptide hormones (ghrelin, MSH/MC4 respectively) in regulating appetite, food intake and gastro-intestinal functions such as transit with two priorities: Cachexia (severe weight loss), which is often the cause of functional disorders in the elderly, cancer patients and patients with chronic illnesses. Obesity probably one of the most characteristic conditions of the 21 st century worldwide

40 A FAR REACHING PARTNERING NETWORK For several decades Ipsen has established partnerships with universities, collaborating with world-renowned academic research teams. Nowadays, Ipsen continues more than ever to rely on its access to academic institutions as a source of knowledge toward the fundamental understanding of diseases and therefore the identification of suitable targets for therapeutic intervention Four collaborative agreements epitomize Ipsen s expertise in homeostasis: SALK INSTITUTE (La Jolla, California) In January 2008, a partnership agreement was announced with the Salk Institute. The Salk Institute for biological studies is an independent non-profit organization dedicated to fundamental discoveries in life sciences, the improvement of human health and the training of future generations of researchers. This major agreement creates the Ipsen Life Sciences Program at the Salk Institute, by which Ipsen gains access to cutting edge technologies in life sciences and advanced knowledge in the field of proliferative and degenerative diseases. Ipsen and the Salk have been involved in a longstanding partnership, with such discoveries as somatostatin, GHRH...

41 CEA (France) In October 2005, Ipsen signed a letter of intention with the French Atomic Energy Commission (CEA) on research projects covering the treatment of Parkinson s and Alzheimer s diseases using one of the most advanced brain imaging platform in Europe. ERINE (Rotterdam, Netherlands) ERINE (Erasmus Research Institute for NeuroEndocrinology) was created in December Ipsen and the Erasmus University Medical Center Rotterdam extended their alliance by concluding a collaboration agreement to identify and progress therapeutic concepts and innovative products within the fields of endocrinology, diabetes and metabolism. INSERM (France) Ipsen has signed several agreements with Inserm on various research programmes, especially in the treatment of breast and prostate cancer, as well as for endocrinology programmes

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